title: Identification of small exonic CNV from whole-exome sequence data and application to autism spectrum disorder.
abstract: Copy number variation (CNV) is an important determinant of human diversity and plays important roles in susceptibility to disease. Most studies of CNV carried out to date have made use of chromosome microarray and have had a lower size limit for detection of about 30 kilobases (kb). With the emergence of whole-exome sequencing studies, we asked whether such data could be used to reliably call rare exonic CNV in the size range of 1-30 kilobases (kb), making use of the eXome Hidden Markov Model (XHMM) program. By using both transmission information and validation by molecular methods, we confirmed that small CNV encompassing as few as three exons can be reliably called from whole-exome data. We applied this approach to an autism case-control sample (n = 811, mean per-target read depth = 161) and observed a significant increase in the burden of rare (MAF ≤1%) 1-30 kb CNV, 1-30 kb deletions, and 1-10 kb deletions in ASD. CNV in the 1-30 kb range frequently hit just a single gene, and we were therefore able to carry out enrichment and pathway analyses, where we observed enrichment for disruption of genes in cytoskeletal and autophagy pathways in ASD. In summary, our results showed that XHMM provided an effective means to assess small exonic CNV from whole-exome data, indicated that rare 1-30 kb exonic deletions could contribute to risk in up to 7% of individuals with ASD, and implicated a candidate pathway in developmental delay syndromes.
authors.affiliation: Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Poultney
authors.forename: Arthur P
authors.initials: AP
authors.lastname: Goldberg
authors.forename: Elodie
authors.initials: E
authors.lastname: Drapeau
authors.forename: Yan
authors.initials: Y
authors.lastname: Kou
authors.forename: Hala
authors.initials: H
authors.lastname: Harony-Nicolas
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kajiwara
authors.forename: Silvia
authors.initials: S
authors.lastname: De Rubeis
authors.forename: Simon
authors.initials: S
authors.lastname: Durand
authors.forename: Christine
authors.initials: C
authors.lastname: Stevens
authors.forename: Karola
authors.initials: K
authors.lastname: Rehnström
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Avi
authors.initials: A
authors.lastname: Ma'ayan
authors.forename: Menachem
authors.initials: M
authors.lastname: Fromer
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
mesh_terms: D001343:Autophagy / Q000235:genetics; D001483:Base Sequence; D016022:Case-Control Studies; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000235:genetics*; D056915:DNA Copy Number Variations; D059472:Exome; D005091:Exons; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D006801:Humans; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA / Q000379:methods